The long-term objective of the applicant is to elucidate the humoral mechanisms important in the regulation of vascular function and blood pressure in normotension and in the development of hypertension. This proposal is based upon recent findings by the PI and others that: in normal rats, pressor responsiveness to vasopressin (VP) is higher in males than in females during most phases of the estrous cycle; deoxycorticosterone (DOCA)-salt hypertension (a VP-dependent form of hypertension), develops to a greater extent in male than in female rats; and there are marked sex differences in vascular reactivity to VP and phenylephrine (PE) and in vascular prostanoid (PG) and endothelium- derived relaxing factor (EDRF) production in normotension and DOCA-salt hypertension. The objectives of this research proposal are to elucidate the local (endothelial) and systemic (vasoconstrictor) humoral mechanisms in the vasculature underlying sex differences in vascular responsiveness to VP and alpha1-adrenergic agonists in the rat, and to elucidate the role of the gonadal steroids in the sexual dimorphism in these local and systemic humoral mechanisms, both in normotension and in the development of DOCA-salt hypertension. The specific aims of the proposed research are to: 1) Characterize male-female differences in vascular reactivity to VP and PE in the rat aorta and peripheral vasculature in vitro; 2) Determine the role of systemic vasoconstrictor mechanisms (vascular smooth muscle receptors) in male-female differences in vascular reactivity to VP and PE in the rat aorta and peripheral vasculature in vitro; 3) Determine the role of vascular prostanoids as local (endothelial) modulators of vascular function in male-female differences in vascular reactivity to VP and PE in the rat aorta and peripheral vasculature in vitro; 4) Determine the role of endothelium-derived relaxing factor as a local (endothelial) modulator of vascular function in male-female differences in vascular reactivity to VP and PE in the rat aorta and peripheral vasculature in vitro; and 5) Determine the role of the gonadal steroid hormones in the sexual dimorphism in these local and systemic vascular mechanisms in vitro. The proposed research will provide a unique examination of local and systemic vascular mechanisms underlying sexual dimorphism in the humoral regulation of the cardiovascular system, both in normotension and in the development of hypertension. It is well established that the incidence of hypertension (and other cardiovascular disease) is higher in men than in pre- menopausal women, thus the proposed research is directly relevant to human health and cardiovascular disease.